Genetics of Parkinson's Disease and Related Disorders-Identifying Genes and Presymptomatic Markers The role of genetics in Parkinson's disease (PD) is now well established, with three genes identified as causal, and multiple additional loci associated with additional gene discovery efforts underway. We continue to ascertain familial Parkinson's disease in order to facilitate Mendelian and complex gene discovery, through clinical characterization and sample collection of affected, at risk, and unaffected subjects. This is in collaboration with the Laboratory of Neurogenetics NIA (John Hardy, PI, Andrew Singleton) and NHGRI (Robert Nussbaum, PI, Grisel Lopez). We are building a case control series of typical Parkinson's disease (banked at the NINDS Genetics Repository) under a currently existing protocol via NIA. We have a protocol pending at NINDS. Our aim is to get 500 PD cases and 500 controls which will allow a complete genome screen. By virtue of repository submission, these samples will be nationally available to genetics researchers (without any personal identifying information). Identifying more mutations will be valuable in determining the genotype/phenotype relationships. Those families in which no known loci contribute to disease will be used in gene discovery efforts by positional cloning in collaboration with the NIA Laboratory of Neurogenetics (Hardy, Singleton). In addition, we are focusing on collection of cases and families with parkinsonism from ethnic groups other than those with European background. This is important not only from a health disparities but also from a scientific standpoint. Families in which Parkinson's disease occurs in a Mendelian fashion offer a valuable resource for identifying the earliest manifestations of disease, by allowing those at risk to be followed longitudinally in order to identify those features. Identifying such early features of disease will in turn allow tools to be developed for generalized screening tests. The literature suggests possibly useful tools for this purpose; however, rigorous development of suggested tools remains to be done. The first step of such efforts is the general goal of this project.